Vandetanib trifluoroacetate

Vandetanib is a multi-kinase inhibitor that inhibits VEGFR2, VEGFR3, VEGFR1, EGFR, PDGFRβ, Tie-2, and FGFR1 in cell-free assays (IC₅₀s = 40, 110, 1,600, 500, 1,100, 2,500, and 3,600 nM, respectively).^1,2 It also binds to 142 additional kinases in a panel of 442 kinases (K_ds = 4.6-7,900 nM). Vandetanib (1 and 2.5 ?M) induces apoptosis and cell cycle arrest at the G₀/G₁ phase in GEO colon and OVCAR-3 ovarian cancer cells.³ It inhibits proliferation of HAK1-B, KYN-2, and Huh7 hepatocarcinoma cells, as well as human umbilical vein endothelial cells (HUVECs), with IC₅₀ values of 10, 8.1, 9.4, and 7.1 ?M, respectively.⁴ Vandetanib (200 mg/kg) increases survival and decreases tumor angiogenesis and VEGFR2 levels in a D54MG glioblastoma mouse xenograft model.⁵ It reduces tumor growth in a variety of mouse xenograft models, including lung, colon, and breast cancer models, when administered at doses of 25, 50, and 100 mg/kg per day.¹ Formulations containing vandetanib have been used in the treatment of medullary thyroid cancer.

1.Wedge, S.R., Ogilvie, D.J., Dukes, M., et al.ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administrationCancer Res.62(16)4645-4655(2002) 2.Davis, M.I., Hunt, J.P., Herrgard, S., et al.Comprehensive analysis of kinase inhibitor selectivityNat. Biotechnol.29(11)1046-1051(2011) 3.Ciardiello, F., Caputo, R., Damiano, V., et al.Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinaseClin. Cancer Res.9(4)1546-1556(2003) 4.Inoue, K., Torimura, T., Nakamura, T., et al.Vandetanib, an inhibitor of VEGF receptor-2 and EGF receptor, suppresses tumor development and improves prognosis of liver cancer in miceClin. Cancer Res.18(14)3924-3933(2012) 5.Rich, J.N., Sathornsumetee, S., Keir, S.T., et al.ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumorsClin. Cancer Res.11(22)8145-8157(2005)